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AU2019101281A4 - Pyridine-2-carboxylic derivative, and preparation method and use thereof - Google Patents

Pyridine-2-carboxylic derivative, and preparation method and use thereof Download PDF

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AU2019101281A4
AU2019101281A4 AU2019101281A AU2019101281A AU2019101281A4 AU 2019101281 A4 AU2019101281 A4 AU 2019101281A4 AU 2019101281 A AU2019101281 A AU 2019101281A AU 2019101281 A AU2019101281 A AU 2019101281A AU 2019101281 A4 AU2019101281 A4 AU 2019101281A4
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isoxazole
cancer
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pyridine
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Canzhong LU
Jianping Yong
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Xiamen Institute of Rare Earth Materials
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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Abstract

The present invention belongs to the field of medicinal chemistry, and particularly relates to a pyridine-2-carboxylic derivative with a novel structure, and a preparation method and use thereof. The present invention mainly relates to a pyridine-2-carboxylic derivative of formula (I), and a stereoisomer, racemate, tautomer thereof, or a pharmaceutically acceptable salt thereof, a preparation method thereof, and use thereof in preparation of an anticancer drug. m(R1) Z O N\ R2)n (I)

Description

PYRIDINE-2-CARBOXYLIC DERIVATIVE, AND PREPARATION METHOD AND USE THEREOF
TECHNICAL FIELD
The present invention belongs to the field of medicinal chemistry, and particularly relates to a pyridine-2-carboxylic derivative with a novel structure, and a preparation method and use thereof.
BACKGROUND
A cancer has become the most important fatal disease worldwide. The cancer can occur in a variety of organs and tissues at any age, and the main types of cancers that cause death are: a lung cancer, a breast cancer, a colorectal cancer, a prostate cancer, and a stomach cancer.
From the perspective of the composition of the top 10 malignant tumors in urban and rural areas in China in recent years, the incidence of the lung cancer is also the highest. For men, a gastric cancer, a liver cancer, a colorectal cancer, an esophageal cancer and the like are cancers with high incidence; and for women, a breast cancer, a colorectal cancer, a thyroid cancer, and a stomach cancer are also cancers with high incidence. According to statistics: the lung cancer has replaced the liver cancer as the fatal malignant tumor in the first place in China, accounting for 22.7% of all malignant tumor deaths (She J, et al. Chest. 2013, 143(4): 1117-1126). The colon and rectal cancers are collectively referred to as a colorectal cancer, which is a common malignant tumor for the digestive tract. In recent years, the incidence of the colorectal cancer in China has increased at an extremely rapid rate. Nationwide, the colorectal cancer has risen to the fourth place in the incidence of malignant tumors. In some cities with rapid economic development, such as Shanghai, it has ranked second (Li Delu, et al. China Cancer. 2011, 20(6): 413-418).
However, for most cancer patients, the cancer is often in the middle to late stages when the condition is found, the overall effect of clinical treatment is poor, and especially the continuous emergence of multi-drug resistance makes the cancer treatment difficult. Therefore, it is extremely urgent to develop a novel anticancer drug with high activity and low side effects to meet clinical demands.
The treatment means for cancer include: a surgery, radiation therapy, and chemotherapy. Surgical treatment sometimes fails to eradicate cancer cells, which enables cancer cells to recur and relapse; additionally, the surgical treatment may lead to serious outcomes, for example cervical cancer and bladder cancer surgeries may lead to infertility and sexual dysfunction, etc.; the radiation therapy will hurt normal cells when used in the cancer treatment; and therefore, drug treatment of cancer is a better choice. However, most of the anticancer drugs applied clinically in China are import-dependent and has a high price. Additionally, most of the anticancer drugs still fail to achieve a satisfactory degree of specificity. When a patient undergoes the chemotherapy,
2019101281 23 Oct 2019 normal cells in the body are often killed with poison along with cancer cells, which seriously affects normal physiological functions and is accompanied by many side effects. Therefore, it is necessary to develop a specific anticancer drug with high activity and low side effects to meet clinical demands.
Pyridine derivatives have a broad spectrum of biological activities: a bacteriostatic, anti-inflammatory, cardiovascular-disease treating, hypolipidemic, anti-platelet aggregation, plant growth regulators, and the like activities [(1) Med. Chem. Res., 2014, 23: 1248-1256; (2) Med. Chem. Res., 2014, 23: 1612-1621; Bioorg. Med. Chem. Lett., 2014, 24:1209-1213; Eur. J. Med. Chem., 2014, 73:243-249; Med. Chem. Res., 2013, 22: 3663-3674], The patent document CN1953748A also had reported that a nicotinic acid derivative has the activity for preventing and treating cancers; and the patent document CN101210012A had reported that the nicotinic acid derivative has hypoglycemic, hypolipidemic, hypotensive, anti-cancer, bacteriostatic, antiviral and the like activities. However, the biological activities of the above drugs still need further improvement.
SUMMARY
An objective of the present invention is to provide an isoxazole-heterocyclic-containing pyridine-2-carboxylic derivative of formula (I), and a preparation method and use thereof. The activity studies showed that, the compounds of this type have strong inhibitory activity against a human lung cancer cell line A549, a colorectal cancer cell line HCT-116 and a breast cancer cell line MCF-7. It can be used as a candidate compound or lead compound for anticancer drugs.
The present invention is achieved by the following technical solutions: a pyridine-2-carboxylic derivative of formula (I), a stereoisomer, racemate, tautomer thereof, or a pharmaceutically acceptable salt thereof,
where:
Z is selected from O, S, NR3, where R3 is hydrogen or a Ci-Ce alkyl;
Ri is selected from halogen, a Ci-Ce alkyl, a Ci-Ce alkoxy, a halogenated Ci-Ce alkyl, an aryl, an aryloxy, a heteroaryl, a heteroaryloxy, a heterocyclic group, and a heterocyclic oxy group;
R2 is selected from a Ci-Ce alkyl, a Ci-Ce alkoxy, a halogenated Ci-Ce alkyl, a cyano, and a nitro;
m is an integer from 0-4;
2019101281 23 Oct 2019 n is an integer from 0-5;
with the proviso that m and n cannot be 0 at the same time, and when m is 0, R2 is not selected from halogen, a Ci-Ce alkyl, Ci-Ce alkoxy, or when n is 0, Ri is not selected from a Ci-C6 alkyl.
According to a preferred embodiment of the present invention, in the formula (I):
Z is selected from O and NH;
Ri is selected from fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl, phenoxy;
R2 is selected from fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, nitro or trifluoromethyl;
m is an integer of 0, 1 and 2; n is an integer of 0, 1,2 and 3;
with the proviso that m and n cannot be 0 at the same time, and when m is 0, R2 is not selected from fluorine, chlorine, methoxy, methyl, or when n is 0, Ri is not selected from methyl.
Preferably, Ri is a substituent at position 5 and/or position 6 on a 2-pyridyl group.
Preferably, R2 is a substituent at position 4 on a 1-phenyl group.
As an example, the pyridine-2-carboxylic derivative of formula (I) is selected from any one of the following compounds:
2019101281 23 Oct 2019
2019101281 23 Oct 2019
YP-57
YP-69
ΥΡ-71
ΥΡ-114
2019101281 23 Oct 2019
YP-96
YP-97
ΥΡ-98
2019101281 23 Oct 2019
The pyridine-2-carboxylic derivative of formula (I) may be selected to form a pharmaceutically acceptable salt together with a pharmaceutically acceptable acid, respectively. The term a pharmaceutically acceptable salt includes, but not limited to, salts formed with inorganic acids, such as hydrochlorides, phosphates, diphosphates, hydrobromides, sulfates, sulfinates, nitrates, and the like salts; also includes salts formed with organic acids such as lactic acid, oxalic acid, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, sulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, trifluoroacetic acid, or an amino acid and alkanoate such as acetate, a salt of HOOC-(CH2)s-COOH, and the like salts, where s is 0-4. Similarly, a pharmaceutically acceptable cation includes, but is not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.
The present invention also provides a pharmaceutical composition, which includes a therapeutically effective amount of at least one of a compound of formula (I), a stereoisomer, racemate, tautomer thereof, or a pharmaceutically acceptable salt thereof.
According to an embodiment of the present invention, the pharmaceutical composition further includes at least one pharmaceutically acceptable adjuvant; the adjuvant may be an inert and non-toxic excipient, carrier or diluent, and for example, the adjuvant is one, two, or more
2019101281 23 Oct 2019 selected from: a disintegrant, a glidant, a lubricant, a filler, a binder, a colorant, an effervescent agent, a flavoring agent, a preservative, a coating material, etc.
The present invention further provides a pharmaceutical formulation including at least one of the compound of formula (I), the stereoisomer, racemate, tautomer thereof, or the pharmaceutically acceptable salt thereof of the present invention.
According to an embodiment of the present invention, preferably the formulation is a solid oral formulation, a liquid oral formulation or an injection.
According to an embodiment of the present invention, the formulation is selected from a tablet (a dispersible tablet, an enteric-coated tablet, a chewable tablet, and an orally disintegrating tablet), a capsule, a granule, an oral solution, water for needle injection, freeze-dried powder for needle injection, large infusion or small infusion.
The present invention also provides the use of at least one of the pyridine-2-carboxylate derivative of formula (I), the stereoisomer, racemate, tautomer thereof, or the pharmaceutically acceptable salt thereof in preparation of an anticancer drug.
According to an embodiment of the present invention, the cancer is a cancer associated with EGFR overexpression and/or hyperactivity.
Preferably, the cancer is selected from: an intestinal cancer, a bladder cancer, an ovarian cancer, a breast cancer, a gastric cancer, an esophageal cancer, a lung cancer, a head and neck cancer, a colon cancer, a pharyngeal cancer and a pancreatic cancer, etc.
Still preferably, the cancer is selected from a non-small cell lung cancer (NSCLC), intestinal cancer, the intestinal cancer, the breast cancer.
The present invention also provides a method for preparing the pyridine-2-carboxylic derivative of formula (I), including the steps of:
reacting a compound of formula (1-1) with a compound of formula (1-2) to obtain a compound of formula (I),
where, Ri, R2, Z, m, n independently have the definitions described above; and X is selected from a leaving group, any functional group in the formula (1-1) and the formula (1-2) can be protected if protection is desired;
and then, if necessary (in any order):
2019101281 23 Oct 2019 (1) removing any protective agent, and (2) forming a pharmaceutically acceptable salt of the compound of formula (I).
According to an embodiment of the present invention, the reaction temperature is from -20°C to a reflux condition, preferably from 0°C to a room temperature condition.
According to an embodiment of the present invention, the reaction is carried out in an organic solvent selected from benzene, toluene, xylene, dichloromethane, chloroform, acetonitrile, dioxane, tetrahydrofuran or DMF.
According to an embodiment of the present invention, the reaction is carried out in the presence of a basic catalyst selected from organic or inorganic bases, where the organic base is preferably triethylamine, tripropylamine, DMAP, tert-butanol potassium or the like; and the inorganic base is preferably potassium carbonate, sodium hydride, sodium carbonate or the like.
Definition and Description of Terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skills in the art.
When the numerical range stated in the specification and claims of this application is defined as an integer, it should be understood as two endpoints of the range and each integer within the range are recited. For example, an integer from 0-4 should be understood as that each integer of 0, 1,2, 3, and 4 is recited.
The Ci-Ce alkyl refers to a linear or branched alkyl having 1-6 carbon atoms, and the Ci-Ce alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, neopentyl.
The Ci-Ce alkoxy refers to a -O-Ci-Ce alkyl, where the Ci-Ce alkyl is as defined above.
The halogenated Ci-Ce alkyl refers to a group that is formed by substituting any one, two or more Hs on the carbon chain of the aforementioned Ci-Ce alkyl with a halogen.
The aryl refers to a monocyclic or polycyclic aromatic group having 6-20 (preferably 6-14) carbon atoms, and representative aryl groups include phenyl, naphthyl, anthryl, pyrenyl and the like.
The aryloxy refers to an -O-aryl group, where the aryl is as defined above.
The heteroaryl refers to a monocyclic or polycyclic aromatic group having 6-20 carbon atoms and 1-4 heteroatoms selected from N, S, and O, and representative heteroaryl groups include: thienyl, furanyl, pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, thiazolyl, indolyl, azanaphthyl, azaanthryl, azapyrenyl, and the like.
The heteroaryloxy refers to an -O-heteroaryl, where the heteroaryl is as defined above.
The heterocyclic group refers to a monocyclic or polycyclic non-aromatic group having 3-20 carbon atoms and 1-4 heteroatoms selected from N, S, and O. In particular, the heterocyclic group
2019101281 23 Oct 2019 may include, but not limited to, a 4-membered ring, such as azetidine or oxetane; a 5-membered ring, such as tetrahydrofuranyl, dioxolenyl, pyrrolidyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring, such as a diazepanyl group. Optionally, the heterocyclic group can be benzofused. The heterocyclic group may be bicyclic, for example but not limited to a 5,5-membered ring, such as a hexahydrocyclopentano[c]pyrrol-2(lH)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl ring.
The heterocyclyloxy group refers to an -O-heterocyclic group, where the heterocyclic group is as defined above.
The term an effective amount refers to a dosage of the at least one compound and/or at least one pharmaceutically acceptable salt that is effective to treat a disease or condition in an individual. In the case of cancer, the effective amount can reduce the number of cancer or tumor cells; reduce the size of a tumor; inhibit or prevent the invasion of tumor cells into peripheral organs, for example, spreading of tumors into soft tissues or bones; inhibit or prevent metastasis of a tumor; or prevent the growth of a tumor; alleviate one or more symptoms associated with a cancer to some extent; reduce incidence and mortality; improve life quality; or a combination of the above effects. The effective amount can be a dosage that reduces the symptoms of a disease by inhibiting EGFR activity. For cancer treatment, the effect of an in vivo experiment can be measured by evaluating, for example, a survival, time to disease progression (TDP), a response rate (RR), a duration of response, and/or life quality.
Those skilled in the art have recognized that the effective amount can vary with the route of administration, the dosage of an excipient, and the combined administration with other drugs.
The term effective amount can also refer to a dose of the at least one compound and/or at least one pharmaceutically acceptable salt thereof that is effective to inhibit EGFR overexpression and/or hyperactivity.
Beneficial effects
The compound of the present invention has anti-tumor and anticancer activities, and especially has strong inhibitory activity against a human lung cancer cell line A549, a colorectal cancer cell line HCT116 and a breast cancer cell line MCF-7. The compound YP-20 has a strong inhibitory activity against all of the three tumor cell lines, where it has an inhibitory activity against the A549 cells comparable to that of the positive drug gefitinib; and the compound YP-51 has a strong inhibitory activity against all of the three tumor cell lines, where it has an inhibitory activity against the lung cancer cell line A549 that is 1.0 χ 1011 times greater than that of the positive drug gefitinib. The specific results are shown in Tables 3, 4 and 5 for activity testing
2019101281 23 Oct 2019 results in Embodiment 4.
Therefore, the compound of the present invention has a broad spectrum of anticancer and anti-tumor activities and can be used as a drug candidate or lead compound for treating tumors and cancers.
DETAILED DESCRIPTION
The present invention is further described below with reference to embodiments. It should be noted that, the following embodiments are not intended to limit the claimed scope of the present invention, and any modifications made on the basis of the present invention does not depart from the spirit of the present invention.
The synthesis processes of an intermediate and a target compound are illustrated by the representatives in the embodiments, and the synthesis processes of the remaining intermediates and target compounds are the same as those of the representative compounds.
Instruments and Reagents:
An AVANCE III nuclear magnetic resonance spectrometer (400MHz, DMSO-de, TMS is used as an internal standard), an ion-trap liquid chromatograph mass spectrometer (DECAX-30000 LCQ Deca XP), a wavelength-adjustable microplate reader (Molecular Devies SPECTRAMAX190), a wavelength-adjustable microplate reader (Molecular Devies SPECTRAMAX190). Chemical reagents are all commercial available analytically-pure or chemically-pure reagents, RPMI1640 is purchased from Gibco, thiazolyl blue [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT) is purchased from Sigma, other reagents are all commercial available analytically-pure reagents and are not treated before use unless otherwise specified, and tetrahydrofuran is treated with a dry molecular sieve before use.
Embodiment 1 Synthesis of an intermediate 3-substituted phenyl-5-hydroxymethyl-isoxazole (II) or an intermediate 3-substituted phenyl-5-aminomethyl-isoxazole (III):
It was prepared by subjecting substituted benzaldehyde as a raw material to synthesis of ruthenium, a 1,3-dipolar cycloaddition reaction, a methanesulfonyl esterification reaction, azidation, and a reduction reaction (R2 and n are as described above), and the details were shown as the following process:
2019101281 23 Oct 2019
Zn/ NH4CI /N . p
reflux (Hl) ,nh2
For the specific synthetic processes of the intermediate 3-substituted
phenyl-5-hydroxymethyl-isoxazole (II) or an intermediate 3-substituted phenyl-5-aminomethyl-isoxazole (III), see patent documents CN103360382A, CN103664991A and CN103601762A for details, the entire content of each of which is incorporated by reference herein.
Embodiment 2 Synthesis of pyridine-2-carboxylate derivative (1-1) of Formula (I)
The reactions of 5-bromo-pyridine-2-carboxylic acid and
3-(4-chlorophenyl)-5-hydroxymethyl-isoxazole was taken as an example for illustration:
Synthesis of [(3-(4-chlorophenyl)-isoxazole-5-yl)-methyl]-5-bromo-pyridine-2-carboxylate (YP-51)
Added into a 50 mL round bottom flask were 0.202 g (1 mmol) 5-bromo-pyridine-2-carboxylic acid and 0.206 g (1 mmol) DCC, added with 10 mL of dry THF, and subjected to a reaction in ice bath under stirring for 30 min, and then the reaction system was added dropwise with the solution of 0.175 g (1 mmol)
2019101281 23 Oct 2019
5-hydroxymethyl-3-(4-chlorophenyl)-isoxazole and 0.209 g (1 mmol) DMAP in 10 mL THF slowly, subjected to a reaction in ice bath under stirring for 30 min, and then warmed to room temperature naturally for reaction. After the TLC detection reaction was completed, the reaction solution was concentrated in vacuo, and the residue was directly separated on a column (at F(petroleum ether): F(ethyi acetate) = 5:1-2:1) to give the target compound [(3-(4-chlorophenyl)-isoxazole-5-yl)-methyl]-5-bromo-pyridin-2-carboxylate (YP-51).
Embodiment 3 Synthesis of pyridine-2-carboxylic acid amide derivative (1-2) of formula (I) The reactions of 5-bromo-pyridine-2-carboxylic acid and
3-(4-chlorophenyl)-5-aminomethyl-isoxazole was taken as an example for illustration:
Synthesis of
A[(3-(4-chlorophenyl)-isoxazole-5-yl)-methyl]-5-bromo-pyridine-2-carboxamide (YP-108)
O
Added into a 50 mL round bottom flask were 0.202 g (1 mmol) 5-bromo-pyridine-2-carboxylic acid, 0.206 g (1 mmol)DCC and 0.135 g (1 mmol) HOBT, added with 10 mL of dry THF, and subjected to a reaction in ice bath under stirring for 30 min, and then the reaction system was added dropwise with the solution of 0.174 g (1 mmol) 5-aminomethyl-3-(4-chlorophenyl)-isoxazole and 0.208 g (1 mmol) DMAP in 10 mL THF slowly, subjected to a reaction in ice bath under stirring for 30 min, and then warmed to room temperature naturally for reaction. After the TLC detection reaction was completed, the reaction solution was concentrated in vacuo, and the residue was directly separated on a column (at V(petroleum ether): L ethyl acetate) = 5:1-2:1) to give the target compound
A[(3-(4-chlorophenyl)-isoxazole-5-yl)-methyl]-5-bromo-pyridin-2-carboxamide (YP-108).
Referring to the above Embodiments, the present application also prepared the compounds as shown in the following tables. The characterization data of the compounds in the aforementioned Embodiments and tables are as follows:
Table 1-Mass spectrometric data
Number MS {m/e, 100%) Number MS {m/e, 100%)
YP-3 308 ([M]+, 60) YP-4 337 ([M+l]+, 100)
2019101281 23 Oct 2019
YP-5 322 ([Μ]+, 80) ΥΡ-8 311 ([Μ+1]+, 90)
YP-7 311 ([Μ+1]+, 100) ΥΡ-10 348 ([Μ]+, 90)
ΥΡ-9 348 ([Μ]+, 100) ΥΡ-12 299 ([Μ+1]+, 100)
ΥΡ-15 351 ([Μ+2]+, 100) ΥΡ-14 315 ([Μ+1]+, 80)
ΥΡ-17 359 ([Μ]+, 100) ΥΡ-16 359 ([Μ]+, 100)
ΥΡ-19 325 ([Μ]+, 100) ΥΡ-18 359 ([Μ]+, 80)
ΥΡ-21 335([Μ+23]+, 5) ΥΡ-20 321 ([Μ+23]+, 68)
ΥΡ-23 355 ([Μ+1]+, 78) ΥΡ-22 327([Μ+1]+, 20)
ΥΡ-25 329 ([Μ+1]+, 5) ΥΡ-24 341 ([Μ+1]+, 60)
ΥΡ-27 329 ([Μ+1]+, 100) ΥΡ-26 328 ([Μ]+, 20)
ΥΡ-29 367 ([Μ+Η]+, 30) ΥΡ-28 366 ([Μ]+, 30)
ΥΡ-31 316 ([Μ]+, 80) ΥΡ-30 316 ([Μ]+, 30)
ΥΡ-33 355([Μ+23]+, 10) ΥΡ-32 332 ([Μ]+, 10)
ΥΡ-35 416 ([Μ+39]+, 5) ΥΡ-34 369([Μ+2]+, 70)
ΥΡ-37 377 ([Μ]+, 70) ΥΡ-36 377 ([Μ]+, 15)
ΥΡ-39 398 ([Μ+39]+, 10) ΥΡ-38 344 ([Μ+1]+, 50)
ΥΡ-41 387 ([Μ]+, 50) ΥΡ-40 391 ([Μ+18]+, 10)
ΥΡ-43 402 ([Μ+1]+, 80) ΥΡ-42 415 ([Μ]+, 70)
ΥΡ-45 389 ([Μ]+, 80) ΥΡ-44 389 ([Μ]+, 100)
ΥΡ-47 427 ([Μ]+, 100) ΥΡ-46 389 ([Μ]+, 80)
ΥΡ-49 337 ([Μ]+, 100) ΥΡ-48 427 ([Μ]+, 80)
ΥΡ-51 394 ([Μ+1]+, 50) ΥΡ-50 337 ([Μ]+, 80)
ΥΡ-53 428 ([Μ]+, 100) ΥΡ-52 393 ([Μ]+,100)
ΥΡ-55 438 ([Μ]+, 80) ΥΡ-54 438 ([Μ]+,100)
ΥΡ-57 405 ([Μ+1]+, 100) ΥΡ-56 438 ([Μ]+, 100)
ΥΡ-61 336 ([Μ+1]+, 100) ΥΡ-60 308 ([Μ+1]+, 60)
ΥΡ-63 310 ([Μ+1]+, 80) ΥΡ-62 322 ([Μ+1]+, 80)
2019101281 23 Oct 2019
YP-65 310([M+l]+, 90) YP-64 310([M+l]+, 100)
YP-67 348 ([M+l]+, 90) YP-66 348 ([M+l]+, 100)
YP-69 298 ([M+l]+, 100) YP-72 350 ([M+l]+, 100)
YP-71 314([M+1]+, 80) YP-74 359 ([M+l]+, 80)
YP-73 359([M+1]+, 100) YP-76 325 ([M+l]+, 100)
YP-75 359 ([M+l]+, 80) YP-78 334 ([M+23]+, 5)
YP-77 320 ([M+23]+, 68) YP-80 354 ([M+l]+, 78)
YP-79 326 ([M+l]+, 20) YP-82 328 ([M+l]+, 5)
YP-81 340 ([M+l]+, 60) YP-84 328 ([M+l]+, 100)
YP-83 328 ([M+l]+, 20) YP-86 366 ([M+l]+, 30)
YP-85 366 ([M+l]+, 30) YP-88 316([M+1]+, 80)
YP-87 316([M+1]+, 30) YP-90 354 ([M+23]+, 10)
YP-89 332 ([M+l]+, 10) YP-92 377 ([M+l]+, 5)
YP-91 367 ([M+l]+, 70) YP-94 343 ([M+l]+, 50)
YP-93 377 ([M+l]+, 70) YP-96 390([M+18]+, 10)
YP-95 397 ([M+39]+, 10) YP-98 415 ([M+l]+, 70)
YP-97 387 ([M+l]+, 50) YP-100 389 ([M+l]+, 100)
YP-99 401 ([M+l]+, 80) YP-102 389 ([M+l]+, 80)
YP-101 389 ([M+l]+, 80) YP-104 427 ([M+l]+, 80)
YP-103 427 ([M+l]+, 100) YP-106 337 ([M+l]+, 80)
YP-105 337 ([M+l]+, 100) YP-108 393 ([M+l]+,100)
YP-107 393 ([M+l]+, 50) YP-110 438 ([M+l]+,100)
YP-109 428 ([M+l]+, 100) YP-112 438 ([M+l]+, 100)
YP-111 438 ([M+l]+, 80) YP-114 279 ([M+l]+, 80)
YP-113 404 ([M+l]+, 100)
Table 2-*H NMR data
Number *H NMR (400 MHz, DMSO-t/e)
2019101281 23 Oct 2019
YP-3 1.28 (t, 7=2.3 Hz, 3Η, CH3), 2.66 (q, 7=2.0 Hz, 2H, CH3CH2), 5.48 (s, 2H, isoxazole-CH2), 7.22 (s, 1H, hydrogen on an isoxazole ring), 7.35 (d, 7=7.2 Hz, 2H) 7.74 (d, 7=7.5 Hz, 2H), 7.88-7.89 (m, 1H), 7.98-7.80 (m, 1H), 8.29 (d, 7=2.8 Hz, 1H), 8.83 (d, 7=2.2 Hz, 1H).
YP-4 1.35 (s, 9H, 3CH3), 5.48 (s, 2H, isoxazole-CH2), 7.22 (s, 1H, hydrogen on an isoxazole ring), 7.38 (d, 7=7.2 Hz, 2H) 7.71 (d, 7=7.5 Hz, 2H), 7.88-7.98 (m, 2H), 8.29 (d, 7=2.8 Hz, 1H), 8.83 (d, 7=2.2 Hz, 1H).
ΥΡ-5 2.34 (s, 3H, CH3), 2.59 (s, 6H, 2CH3), 5.48 (s, 2H, isoxazole-CH2), 7.05 (s, 2H), 7.18 (s, 1H, hydrogen on an isoxazole ring), 7.88-7.98 (m, 2H), 8.29 (d, 7=2.8 Hz, 1H), 8.83 (d, 7=2.2 Hz, 1H).
ΥΡ-7 3.85 (s, 3H, OCH3), 5.48 (s, 2H, isoxazole-CH2), 7.05-7.07 (m, 2H), 7.18 (s, 1H, hydrogen on an isoxazole ring), 7.30-7.31 (m, 1H), 7.88-7.98 (m, 2H), 8.29 (d, 7=2.8 Hz, 1H), 8.32-8.33 (m, 1H), 8.83 (d, 7=2.2 Hz, 1H).
ΥΡ-8 3.85(s, 3H, OCH3), 5.48 (s, 2H, isoxazole-CH2), 7.01 (d, J= 2.3 Hz, 1H), 7.15 (s, 1H, hydrogen on an isoxazole ring), 7.35-7.40 (m, 3H), 7.88-7.89 (m, 2H), 8.29 (d, 7=2.8 Hz, 1H), 8.83 (d, 7=2.2 Hz, 1H).
ΥΡ-9 5.48 (s, 2H, isoxazole-CH2), 7.15 (s, 1H, hydrogen on an isoxazole ring), 7.68 (d, 7=7.2 Hz, 2H) 7.73 (d, 7=7.5 Hz, 2H), 7.88-7.98 (m, 2H), 8.29 (d, 7=2.8 Hz, 1H), 8.83 (d, 7=2.2 Hz, 1H).
ΥΡ-10 5.48 (s, 2H, isoxazole-CH2), 7.15 (s, 1H, hydrogen on an isoxazole ring), 7.34-7.35 (m, 1H), 7.51-7.52 (m, 1H), 7.61 (d, J= 2.5 Hz, 1H), 7.68 (d, 7=2.3 Hz, 1H), 7.88-7.98 (m, 2H), 8.29 (d, 7=2.8 Hz, 1H), 8.83 (d, 7=2.2 Hz, 1H).
ΥΡ-12 5.48 (s, 2H, isoxazole-CH2), 7.15 (s, 1H, hydrogen on an isoxazole ring), 7.28-7.29 (m, 1H), 7.49-7.50 (m, 1H), 7.71-7.72 (m, 1H), 7.77-7.78 (m, 1H), 7.88-7.98(m, 2H), 8.29 (d, 7=2.8 Hz, 1H), 8.83 (d, 7=2.2 Hz, 1H).
ΥΡ-14 5.48 (s, 2H, isoxazole-CH2), 7.15 (s, 1H, hydrogen on an isoxazole ring), 7.28-7.29 (m, 1H), 7.49-7.50 (m, 1H), 7.71-7.72 (m, 1H), 7.77-7.78 (m, 1H), 7.88-7.98(m, 2H),
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8.29 (d, 7=2.8 Hz, 1Η), 8.83 (d, 7=2.2 Hz, 1H).
YP-15 5.48 (s, 2H, isoxazole-CH2), 7.15 (s, 1H, hydrogen on an isoxazole ring), 7.43 (d, 7=2.6 Hz, 1H), 7.50 (s, 1H), 7.88-7.98 (m, 2H), 8.03 (d, 7=3.2 Hz, 1H), 8.29 (d, 7=2.8 Hz, 1H), 8.83 (d, 7=2.2 Hz, 1H).
YP-16 5.48 (s, 2H, isoxazole-CH2), 7.15 (s, 1H, hydrogen on an isoxazole ring), 7.30 (d, 7=7.2 Hz, 2H), 7.88-7.89 (m, 2H), 8.15 (d, 7=7.5 Hz, 2H), 8.29 (d, 7=2.8 Hz, 1H), 8.83 (d, 7=2.2 Hz, 1H).
ΥΡ-17 5.48 (s, 2H, isoxazole-CH2), 7.15 (s, 1H, hydrogen on an isoxazole ring), 7.28-7.29 (m, 1H), 7.49-7.50 (m, 1H), 7.71-7.72 (m, 1H), 7.77-7.78 (m, 1H), 7.88-7.98 (m, 2H), 8.29 (d, 7=2.8 Hz, 1H), 8.83 (d, 7=2.2 Hz, 1H).
ΥΡ-18 5.48 (s, 2H, isoxazole-CH2), 7.15 (s, 1H, hydrogen on an isoxazole ring), 7.40-7.42 (m, 1H), 7.46 (s, 1H), 7.56 (d, 7=2.5 Hz, 1H), 7.73 (d, 7=2.4 Hz, 1H), 7.88-7.98 (m, 2H), 8.29 (d, 7=2.8 Hz, 1H), 8.83 (d, 7=2.2 Hz, 1H).
ΥΡ-19 5.48 (s, 2H, isoxazole-CH2), 7.15 (s, 1H, hydrogen on an isoxazole ring), 7.88-7.89 (m, 2H), 8.06 (d, 7=7.2 Hz, 2H), 8.29 (d, 7=2.8 Hz, 1H), 8.35 (d, 7=7.5 Hz, 2H), 8.83 (d, 7=2.2 Hz, 1H).
ΥΡ-20 5.48 (s, 2H, isoxazole-CH2), 7.40-7.43 (m, 4H), 7.76-7.79 (m, 2H), 7.97-7.80 (m, 1H), 8.08-8.14 (m, 1H).
ΥΡ-21 2.24 (s, 3H, CH3), 5.46 (s, 2H, isoxazole-CH2), 7.08 (s, 1H, hydrogen on an isoxazole ring), 7.22 (d, 2H, 7=8.0 Hz), 7.40-7.43 (m, 1H), 7.67 (d, 2H, 7=8.4 Hz), 7.97-7.99 (m, 1H), 8.08-8.14 (m, 1H).
ΥΡ-22 1.25 (t, J= 2.4 Hz, 3H, CH3), 2.58 (q, J= 3.2 Hz, 2H, CH2CH3), 5.46 (s, 2H, isoxazole-CH2), 7.08 (s, 1H, hydrogen on an isoxazole ring), 7.32 (d, 2H, 7=8.0 Hz), 7.74 (d, 2H, 7=8.4 Hz), 7.76-7.77 (m, 1H), 7.97-7.99 (m, 1H), 8.08-8.14 (m, 1H).
ΥΡ-23 1.35 (s, 9H, 3CH3), 5.46 (s, 2H, isoxazole-CH2), 7.08 (s, 1H, hydrogen on an isoxazole ring), 7.32 (d, 2H, 7=8.0 Hz), 7.74 (d, 2H, 7=8.4 Hz), 7.76-7.77 (m, 1H), 7.97-7.99 (m, 1H), 8.08-8.14 (m, 1H).
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YP-24 2.34 (s, 3Η, CH3), 2.59 (s, 6Η, 2CH3), 5.46 (s, 2H, isoxazole-CH2), 7.08 (s, 1H, hydrogen on an isoxazole ring), 5.46 (s, 2H, oxazole-CH2), 7.08 (s, 1H, hydrogen on an oxazole ring), 6.97 (s, 2H), 7.76-7.77 (m, 1H), 7.97-7.99 (m, 1H), 8.08-8.14 (m, 1H).
YP-25 3.70 (s, 3H, OCH3), 5.44 (s, 2H, isoxazole-CH2), 6.95 (d, 2H, J= 8.8 Hz), 7.05 (s, 1H, hydrogen on an isoxazole ring), 7.40-7.43 (m, 1H), 7.72 (d, 2H, J= 8.8 Hz), 7.96-7.98 (m, 1H), 8.08-8.14 (m, 1H).
ΥΡ-26 3.70 (s, 3H, OCH3), 5.44 (s, 2H, isoxazole-CH2), 7.05 (s, 1H, hydrogen on an isoxazole ring), 7.05-7.07 (m, 2H), 7.30-7.32 (m, 1H), 7.76-7.77 (m, 1H), 7.97-7.99 (m, 1H), 8.08-8.14 (m, 1H).
ΥΡ-27 3.70 (s, 3H, OCH3), 5.44 (s, 2H, isoxazole-CH2), 7.05 (s, 1H, hydrogen on an isoxazole ring), 6.95-6.97 (m, 1H), 7.35-7.40 (m, 3H), 7.76-7.77 (m, 1H), 7.97-7.99 (m, 1H), 8.08-8.14 (m, 1H).
ΥΡ-28 5.44 (s, 2H, isoxazole-CH2), 7.05 (s, 1H, hydrogen on an isoxazole ring), 7.68 (d, 2H, J= 8.5 Hz), 7.72 (d, 2H, 7=8.8 Hz), 7.76-7.77 (m, 1H), 7.97-7.99 (m, 1H), 8.08-8.14 (m, 1H).
ΥΡ-29 5.44 (s, 2H, isoxazole-CH2), 7.05 (s, 1H, hydrogen on an isoxazole ring), 7.34-7.36 (m, 1H), 7.51-7.53 (m, 1H), 7.61 (d, 7=2.8 Hz, 1H), 7.68 (d, 7=3.2 Hz, 1H), 7.76-7.77 (m, 1H), 7.97-7.99 (m, 1H), 8.08-8.14 (m, 1H).
ΥΡ-30 5.47 (s, 2H, isoxazole-CH2), 7.15 (s, 1H, hydrogen on an isoxazole ring), 7.39-7.46 (m, 1H), 7.47 (d, 2H, J= 6.4 Hz), 7.80 (d, 2H, J= 6.8 Hz), 7.96-7.98 (m, 1H), 8.07-8.13 (m, 1H).
ΥΡ-31 5.50 (s, 2H, isoxazole-CH2), 6.99 (s, 1H, hydrogen on an isoxazole ring), 7.35-7.45 (m, 3H), 7.51-7.53 (m, 1H), 7.58-7.60 (m, 1H), 7.96-7.98 (m, 1H), 8.07-8.13 (m, 1H).
ΥΡ-32 5.47 (s, 2H, isoxazole-CH2), 7.15 (s, 1H, hydrogen on an isoxazole ring), 7.39-7.46 (m, 1H), 7.47 (d, 2H, J= 6.4 Hz), 7.80 (d, 2H, 7=6.8 Hz), 7.96-7.98 (m, 1H), 8.07-8.13 (m, 1H).
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YP-33 5.50 (s, 2Η, isoxazole-CHY), 6.99 (s, 1Η, hydrogen on an isoxazole ring), 7.35-7.45 (m, 3H), 7.51-7.53 (m, 1H), 7.58-7.60 (m, 1H), 7.96-7.98 (m, 1H), 8.07-8.13 (m, 1H).
YP-34 5.50 (s, 2H, isoxazole-CFh), 6.99 (s, 1H, hydrogen on an isoxazole ring), 7.43 (d, 7=2.8 Hz, 1H), 7.50 (s, 1H), 7.58-7.60 (m, 1H), 8.03 (d, 7=2.6 Hz, 1H), 7.97-7.99 (m, 1H), 8.08-8.14 (m, 1H).
ΥΡ-35 5.46 (s, 2H, isoxazole-CH2), 7.14 (s, 1H, hydrogen on an isoxazole ring), 7.39-7.41 (m, 1H), 7.61 (d, 2H, 7=8.8 Hz), 7.73 (d, 2H, 7=8.4 Hz), 7.95-7.97 (m, 1H), 8.07-8.12 (m, 1H).
ΥΡ-36 5.50 (s, 2H, isoxazole-CH2), 6.99 (s, 1H, hydrogen on an isoxazole ring), 7.35-7.45 (m, 3H), 7.51-7.53 (m, 1H), 7.58-7.60 (m, 1H), 7.96-7.98 (m, 1H), 8.07-8.13 (m, 1H).
ΥΡ-37 5.50 (s, 2H, isoxazole-CH2), 6.99 (s, 1H, hydrogen on an isoxazole ring), 7.40-7.45 (m, 1H), 7.46 (s, 1H), 7.56 (d, 7=3.2 Hz, 1H), 7.73-7.76 (m, 2H), 7.95-7.97 (m, 1H), 8.07-8.12 (m, 1H).
ΥΡ-38 5.50 (s, 2H, isoxazole-CH2), 6.99 (s, 1H, hydrogen on an isoxazole ring), 7.58-7.60 (m, 1H), 8.05 (d, 2H, 7=8.8 Hz), 8.33 (d, 2H, 7=8.4 Hz), 8.44-8.45 (m, 1H), 8.49-8.51 (m, 1H).
ΥΡ-39 5.60 (s, 2H, isoxazole-CH2), 7.28 (s, 1H, hydrogen on an isoxazole ring), 7.51-7.54 (m, 3H), 7.74 (1H, dd, J= 0.8, 0.8 Hz), 7.87-7.91 (m, 2H), 8.40 (1H, dd, J= 2.8, 2.4 Hz), 9.00 (1H, dd, J= 0.4, 0.8 Hz).
ΥΡ-40 2.37 (s, 3H, CH3), 5.58 (s, 2H, isoxazole-CH2), 7.24 (s, 1H, hydrogen on an isoxazole ring), 7.34 (d, 2H, J= 8.0 Hz), 7.74 (d, 1H, 7=8.4 Hz), 7.79 (d, 2H, 7=8.0 Hz), 8.40 (dd, J= 2.0, 2.4 Hz, 1H), 8.99 (d, 1H, J= 2.0 Hz).
ΥΡ-41 1.25 (t, 7=2.3 Hz, 3H, CH3), 2.56 (q, 7=3.2 Hz, 2H, CH3CH2), 5.46 (s, 2H, isoxazole-CH2), 7.08 (s, 1H, hydrogen on an isoxazole ring), 7.34 (d, 2H, 7= 8.0 Hz), 7.74 (d, 2H, J= 8.4 Hz), 7.79 (d, 7=2.5 Hz, 1H), 8.26 (d, 7=3.5 Hz, 1H), 8.94 (s, 1H).
ΥΡ-42 1.35 (s, 9H, 3CH3), 5.46 (s, 2H, isoxazole-CH2), 7.08 (s, 1H, hydrogen on an isoxazole ring), 7.38 (d, 2H, J= 8.0 Hz), 7.72 (d, 2H, J= 8.4 Hz), 7.79 (d, 7=2.5 Hz,
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1Η), 8.26 (d, 7=3.5 Hz, 1Η), 8.94 (s, 1H).
YP-43 2.34 (s, 3H, CH3), 2.56 (s, 6H, 2CH3), 5.46 (s, 2H, isoxazole-CH2), 7.08 (s, 1H, hydrogen on an isoxazole ring), 6.97 (s, 2H), 7.79 (d, 7=2.5 Hz, 1H), 8.26 (d, 7=3.5 Hz, 1H), 8.94 (s, 1H).
YP-44 3.82 (s, 3H, OCH3), 5.57 (s, 2H, isoxazole-CH2), 7.08 (d, 2H, 7=8.8 Hz), 7.21 (s, 1H, hydrogen on an isoxazole ring), 7.73 (d, 1H, 7=8.4 Hz), 7.85 (d, 2H, 7=8.8 Hz), 8.40 (dd, 1H, J= 2.8, 2.4 Hz), 8.99 (d, 1H, J= 2.0 Hz).
ΥΡ-45 3.82 (s, 3H, OCH3), 5.57 (s, 2H, isoxazole-CH2), 7.01 (s, 1H, hydrogen on an isoxazole ring), 7.05-7.07 (m, 2H), 7.30-7.32 (m, 1H), 7.99 (d, J= 2.1 Hz, 1H), 8.26 (d, 7= 1.8 Hz, 1H), 8.32 (d,7= 2.0 Hz, 1H), 8.94 (s, 1H).
ΥΡ-46 3.82 (s, 3H, OCH3), 5.57 (s, 2H, isoxazole-CH2), 7.01 (s, 1H, hydrogen on an isoxazole ring), 7.02 (d, 7=1.8 Hz, 1H), 7.35-7.40 (m, 3H), 7.79 (d, 7=2.5 Hz, 1H), 8.26 (d, 7=3.5 Hz, 1H), 8.94 (s, 1H).
ΥΡ-47 5.58 (s, 2H, isoxazole-CH2), 7.19 (s, 1H, hydrogen on an isoxazole ring), 7.68 (d, 2H, J= 8.4Hz), 7.72 (d, 2H, J= 8.4 Hz), 7.99 (d, 7=2.5 Hz, 1H), 8.26 (d, 7=3.5 Hz, 1H), 8.94 (s, 1H).
ΥΡ-48 5.58 (s, 2H, isoxazole-CH2), 7.19 (s, 1H, hydrogen on an isoxazole ring), 7.34-7.35 (m, 1H), 7.51-7.52 (m, 1H), 7.61 (d, 7=2.3 Hz, 1H), 7.68 (d, J= 2.3 Hz, 1H), 7.99 (d, 7=2.5 Hz, 1H), 8.26 (d, 7=3.5 Hz, 1H), 8.94 (s, 1H).
ΥΡ-49 5.58 (s, 2H, isoxazole-CH2), 7.22 (s, 1H, hydrogen on an isoxazole ring), 7.30 (d, 2H, J= 8.4 Hz), 7.79 (d, 7=2.3 Hz, 1H), 8.15 (d, 2H, J= 8.4 Hz), 8.26 (d, 7=3.5 Hz, 1H), 8.94 (s, 1H).
ΥΡ-50 5.58 (s, 2H, isoxazole-CH2), 7.22 (s, 1H, hydrogen on an isoxazole ring), 7.28-7.29 (m, 1H), 7.49-7.50 (m, 1H), 7.71-7.77 (m, 2H), 7.99 (d, 7=2.5 Hz, 1H), 8.26 (d, 7=3.5 Hz, 1H), 8.94 (s, 1H).
ΥΡ-51 5.61 (s, 2H, isoxazole-CH2), 7.32 (s, 1H, hydrogen on an isoxazole ring), 7.62 (d, 2H, J= 8.4 Hz), 7.74 (d, 1H, J= 8.4 Hz), 7.95 (d, 2H, 7=8.4 Hz), 8.41 (dd, 1H, J= 2.4, 2.4
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Ηζ), 9.01 (t, 1Η, 7=0.4 Hz).
YP-52 5.62 (s, 2Η, isoxazole-CH2), 7.14 (s, 1H, hydrogen on an isoxazole ring), 7.46-7.57 (m, 2H), 7.65 (dd, 1H, J= 1.2, 1.2 Hz), 7.71 (d, 2H, 7=7.6 Hz), 8.38 (dd, 1H, J= 2.4, 2.4 Hz), 8.97 (d, 1H, J= 2.0 Hz).
YP-53 5.62 (s, 2H, isoxazole-CH2), 7.14 (s, 1H, hydrogen on an isoxazole ring), 7.43 (d, 7=2.5 Hz, 1H), 7.50 (s, 1H), 7.99 (d, 7=3.2 Hz, 1H), 8.03 (d, 7=3.4 Hz.lH), 8.26 (d, 7=3.5 Hz, 1H), 8.94 (s, 1H).
ΥΡ-54 5.67 (s, 2H, isoxazole-CH2), 7.38 (s, 1H, hydrogen on an isoxazole ring), 7.79-7.82 (m, 3H), 7.94 (d, 2H, 7=8.8 Hz), 8.47 (dd, 1H, 7=2.4, 2.4 Hz), 9.07 (d, 1H, J= 2.4 Hz).
ΥΡ-55 5.62 (s, 2H, isoxazole-CH2), 7.14 (s, 1H, hydrogen on an isoxazole ring), 7.46-7.57 (m, 2H), 7.65 (dd, 1H, J= 1.2, 1.2 Hz), 7.71 (d, 2H, 7=7.6 Hz), 8.38 (dd, 1H, J= 2.4, 2.4 Hz), 8.97 (d, 1H, J= 2.0 Hz).
ΥΡ-56 5.62 (s, 2H, isoxazole-CH2), 7.14 (s, 1H, hydrogen on an isoxazole ring), 7.40-7.45 (m, 1H), 7.48 (s, 1H), 7.56 (d, 7=2.5 Hz, 1H), 7.72 (d, 7=2.5 Hz, 1H), 7.99 (d, 7=2.5 Hz, 1H), 8.26 (d, 7=3.5 Hz, 1H), 8.94 (s, 1H).
ΥΡ-57 5.62 (s, 2H, isoxazole-CH2), 7.14 (s, 1H, hydrogen on an isoxazole ring), 7.99 (d, 7=2.5 Hz, 1H), 8.05 (d, 2H, 7=7.6 Hz), 8.26 (d, 7=2.5 Hz, 1H), 8.32 (d, 2H, 7=7.6 Hz), 8.94 (s, 1H).
ΥΡ-60 1.28 (t, 7=2.3 Hz, 3H, CH3), 2.66 (q, 7=2.0 Hz, 2H, CH3CH2), 5.48 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.22 (s, 1H, hydrogen on an isoxazole ring), 7.35 (d, 7=7.2 Hz, 2H) 7.74 (d, 7=7.5 Hz, 2H), 7.88-7.89 (m, 1H), 7.98-7.80 (m, 1H), 8.29 (d, 7=2.8 Hz, 1H), 8.83 (d, 7=2.2 Hz, 1H).
ΥΡ-61 1.35 (s, 9H, 3CH3), 5.48 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.22 (s, 1H, hydrogen on an isoxazole ring), 7.38 (d, 7=7.2 Hz, 2H) 7.71 (d, 7=7.5 Hz, 2H), 7.88-7.98 (m, 2H), 8.29 (d, 7=2.8 Hz, 1H), 8.83 (d, 7=2.2 Hz, 1H).
ΥΡ-62 2.34 (s, 3H, CH3), 2.59 (s, 6H, 2CH3), 5.48 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.05 (s, 2H), 7.18 (s, 1H, hydrogen on an isoxazole ring), 7.88-7.98 (m,
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2Η), 8.29 (d, 7=2.8 Hz, 1Η), 8.83 (d, 7=2.2 Hz, 1H).
YP-63 3.83 (s, 3H, 0CH3), 5.48 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.05 (d, J=1.3 Hz, 2H), 7.18 (s, 1H, hydrogen on an isoxazole ring), 7.55 (d, J= 7.3 Hz, 2H), 7.88-7.98 (m, 2H), 8.29 (d, 7=2.8 Hz, 1H), 8.83 (d, 7=2.2 Hz, 1H).
YP-64 3.85 (s, 3H, OCH3), 5.48 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.05-7.07 (m, 2H), 7.18 (s, 1H, hydrogen on an isoxazole ring), 7.30-7.31 (m, 1H), 7.88-7.98 (m, 2H), 8.29 (d, 7=2.8 Hz, 1H), 8.32-8.33 (m, 1H), 8.83 (d, 7=2.2 Hz, 1H).
ΥΡ-65 3.85 (s, 3H, OCH3), 5.48 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.01 (d, J= 2.3 Hz, 1H), 7.15 (s, 1H, hydrogen on an isoxazole ring), 7.35-7.40 (m, 3H), 7.88-7.89 (m, 2H), 8.29 (d, 7=2.8 Hz, 1H), 8.83 (d, 7=2.2 Hz, 1H).
ΥΡ-66 5.48 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.15 (s, 1H, hydrogen on an isoxazole ring), 7.68 (d, 7=7.2 Hz, 2H) 7.73 (d, 7=7.5 Hz, 2H), 7.88-7.98 (m, 2H), 8.29 (d, 7=2.8 Hz, 1H), 8.83 (d, 7=2.2 Hz, 1H).
ΥΡ-67 5.48 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.15 (s, 1H, hydrogen on an isoxazole ring), 7.34-7.35 (m, 1H), 7.51-7.52 (m, 1H), 7.61 (d, 7= 2.5 Hz, 1H), 7.68 (d, 7=2.3 Hz, 1H), 7.88-7.98 (m, 2H), 8.29 (d, 7=2.8 Hz, 1H), 8.83 (d, 7=2.2 Hz, 1H).
ΥΡ-69 5.48 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.15 (s, 1H, hydrogen on an isoxazole ring), 7.28-7.29 (m, 1H), 7.49-7.50 (m, 1H), 7.71-7.72 (m, 1H), 7.77-7.78 (m, 1H), 7.88-7.98(m, 2H), 8.29 (d, 7=2.8 Hz, 1H), 8.83 (d, 7=2.2 Hz, 1H).
ΥΡ-71 5.48 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.15 (s, 1H, hydrogen on an isoxazole ring), 7.28-7.29 (m, 1H), 7.49-7.50 (m, 1H), 7.71-7.72 (m, 1H), 7.77-7.78 (m, 1H), 7.88-7.98 (m, 2H), 8.29 (d, 7=2.8 Hz, 1H), 8.83 (d, 7=2.2 Hz, 1H).
ΥΡ-72 5.48 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.15 (s, 1H, hydrogen on an isoxazole ring), 7.43 (d, 7=2.6 Hz, 1H), 7.50 (s, 1H), 7.88-7.98 (m, 2H), 8.03 (d, 7=3.2Hz, 1H), 8.29 (d, 7=2.8 Hz, 1H), 8.83 (d, 7=2.2 Hz, 1H).
ΥΡ-73 5.48 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.15 (s, 1H, hydrogen on
2019101281 23 Oct 2019
an isoxazole ring), 7.30 (d, 7=7.2 Hz, 2H), 7.88-7.89 (m, 2H), 8.15 (d, 7=7.5 Hz, 2H), 8.29 (d, 7=2.8 Hz, 1H), 8.83 (d, 7=2.2 Hz, 1H).
YP-74 5.48 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.15 (s, 1H, hydrogen on an isoxazole ring), 7.28-7.29 (m, 1H), 7.49-7.50 (m, 1H), 7.71-7.72 (m, 1H), 7.77-7.78 (m, 1H), 7.88-7.98 (m, 2H), 8.29 (d, 7=2.8 Hz, 1H), 8.83 (d, 7=2.2 Hz, 1H).
YP-75 5.48 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.15 (s, 1H, hydrogen on an isoxazole ring), 7.40-7.42 (m, 1H), 7.46 (s, 1H), 7.56 (d, 7=2.5 Hz, 1H), 7.73 (d, 7=2.4 Hz, 1H), 7.88-7.98 (m, 2H), 8.29 (d, 7=2.8 Hz, 1H), 8.83 (d, 7=2.2 Hz, 1H).
ΥΡ-76 5.48 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.15 (s, 1H, hydrogen on an isoxazole ring), 7.88-7.89 (m, 2H), 8.06 (d, J=1.2 Hz, 2H), 8.29 (d, 7=2.8 Hz, 1H), 8.35 (d, 7=7.5 Hz, 2H), 8.83 (d, 7=2.2 Hz, 1H).
ΥΡ-77 5.48 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.40-7.43 (m, 4H), 7.76-7.79 (m, 2H), 7.97-7.80 (m, 1H), 8.08-8.14 (m, 1H).
ΥΡ-78 2.24 (s, 3H, CH3), 5.46 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.08 (s, 1H, hydrogen on an isoxazole ring), 7.22 (d, 2H, 7=8.0 Hz), 7.40-7.43 (m, 1H), 7.67 (d, 2H, 7=8.4 Hz), 7.97-7.99 (m, 1H), 8.08-8.14 (m, 1H).
ΥΡ-79 1.25 (t, J= 2.4 Hz, 3H, CH3), 2.58 (q, J= 3.2 Hz, 2H, CH2CH3), 5.46 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.08 (s, 1H, hydrogen on an isoxazole ring), 7.32 (d, 2H, 7=8.0 Hz), 7.74 (d, 2H, 7=8.4 Hz), 7.76-7.77 (m, 1H), 7.97-7.99 (m, 1H), 8.08-8.14 (m, 1H).
ΥΡ-80 1.35 (s, 9H, 3CH3), 5.46 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.08 (s, 1H, hydrogen on an isoxazole ring), 7.32 (d, 2H, 7=8.0 Hz), 7.74 (d, 2H, 7=8.4 Hz), 7.76-7.77 (m, 1H), 7.97-7.99 (m, 1H), 8.08-8.14 (m, 1H).
ΥΡ-81 2.34 (s, 3H, CH3), 2.59 (s, 6H, 2CH3), 5.46 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.08 (s, 1H, hydrogen on an isoxazole ring), 6.97 (s, 2H), 7.76-7.77 (m, 1H), 7.97-7.99 (m, 1H), 8.08-8.14 (m, 1H).
ΥΡ-82 3.70 (s, 3H, OCH3), 5.44 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 6.95
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(d, 2Η, J= 8.8 Hz), 7.05 (s, 1H, hydrogen on an isoxazole ring), 7.40-7.43 (m, 1H), 7.72 (d, 2H, 7=8.8 Hz), 7.96-7.98 (m, 1H), 8.08-8.14 (m, 1H).
YP-83 3.70 (s, 3H, OCH3), 5.44 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.05 (s, 1H, hydrogen on an isoxazole ring), 7.05-7.07 (m, 2H), 7.30-7.32 (m, 1H), 7.76-7.77 (m, 1H), 7.97-7.99 (m, 1H), 8.08-8.14 (m, 1H).
YP-84 3.70 (s, 3H, OCH3), 5.44 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.05(s, 1H, hydrogen on an isoxazole ring), 6.95-6.97 (m, 1H), 7.35-7.40 (m, 3H), 7.76-7.77 (m, 1H), 7.97-7.99 (m, 1H), 8.08-8.14 (m, 1H).
ΥΡ-85 5.44 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.05 (s, 1H, hydrogen on an isoxazole ring), 7.68 (d, 2H, J= 8.5 Hz), 7.72(d, 2H, J= 8.8 Hz), 7.76-7.77 (m, 1H), 7.97-7.99 (m, 1H), 8.08-8.14 (m, 1H).
ΥΡ-86 5.44 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.05 (s, 1H, hydrogen on an isoxazole ring), 7.34-7.36 (m, 1H), 7.51-7.53 (m, 1H), 7.61 (d, 7=2.8 Hz, 1H), 7.68 (d, 7=3.2 Hz, 1H), 7.76-7.77 (m, 1H), 7.97-7.99 (m, 1H), 8.08-8.14 (m, 1H).
ΥΡ-87 5.47 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.15 (s, 1H, hydrogen on an isoxazole ring), 7.39-7.46 (m, 1H), 7.47 (d, 2H, 7= 6.4 Hz), 7.80 (d, 2H, 7= 6.8 Hz), 7.96-7.98 (m, 1H), 8.07-8.13 (m, 1H).
ΥΡ-88 5.50 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 6.99 (s, 1H, hydrogen on an isoxazole ring), 7.35-7.45 (m, 3H), 7.51-7.53 (m, 1H), 7.58-7.60 (m, 1H), 7.96-7.98 (m, 1H), 8.07-8.13 (m, 1H).
ΥΡ-89 5.47 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.15 (s, 1H, hydrogen on an isoxazole ring), 7.39-7.46 (m, 1H), 7.47 (d, 2H, 7= 6.4 Hz), 7.80 (d, 2H, 7= 6.8 Hz), 7.96-7.98 (m, 1H), 8.07-8.13 (m, 1H).
ΥΡ-90 5.50 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 6.99 (s, 1H, hydrogen on an isoxazole ring), 7.35-7.45 (m, 3H), 7.51-7.53 (m, 1H), 7.58-7.60 (m, 1H), 7.96-7.98 (m, 1H), 8.07-8.13 (m, 1H).
ΥΡ-91 5.50 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 6.99 (s, 1H, hydrogen on
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an isoxazole ring), 7.43 (d, 7=2.8 Hz, 1H), 7.50 (s, 1H), 7.58-7.60 (m, 1H), 8.03 (d, 7=2.6 Hz, 1H), 7.97-7.99 (m, 1H), 8.08-8.14 (m, 1H).
YP-92 5.46 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.14 (s, 1H, hydrogen on an isoxazole ring), 7.39-7.41 (m, 1H), 7.61 (d, 2H, 7=8.8 Hz), 7.73 (d, 2H, 7=8.4 Hz), 7.95-7.97 (m, 1H), 8.07-8.12 (m, 1H).
YP-93 5.50 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 6.99 (s, 1H, hydrogen on an isoxazole ring), 7.35-7.45 (m, 3H), 7.51-7.53 (m, 1H), 7.58-7.60 (m, 1H), 7.96-7.98 (m, 1H), 8.07-8.13 (m, 1H).
ΥΡ-94 5.50 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 6.99 (s, 1H, hydrogen on an isoxazole ring), 7.40-7.45 (m, 1H), 7.46 (s, 1H), 7.56 (d, 7=3.2 Hz, 1H), 7.73-7.76 (m, 2H), 7.95-7.97 (m, 1H), 8.07-8.12 (m, 1H).
ΥΡ-95 5.50 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 6.99 (s, 1H, hydrogen on an isoxazole ring), 7.58-7.60 (m, 1H), 8.05 (d, 2H, 7=8.8 Hz), 8.33 (d, 2H, 7=8.4 Hz), 8.44-8.45 (m, 1H), 8.49-8.51 (m, 1H).
ΥΡ-96 5.60 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.28 (s, 1H, hydrogen on an isoxazole ring), 7.51-7.54 (m, 3H), 7.74 (1H, dd, 7= 0.8, 0.8 Hz), 7.87-7.91 (m, 2H), 8.40 (1H, dd, J= 2.8, 2.4 Hz), 9.00 (1H, dd, J= 0.4, 0.8 Hz).
ΥΡ-97 2.37 (s, 3H, CH3), 5.58 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.24 (s, 1H, hydrogen on an isoxazole ring), 7.34 (d, 2H, J= 8.0 Hz), 7.74 (d, 1H, 7=8.4 Hz), 7.79 (d, 2H, 7=8.0 Hz), 8.40 (dd, J= 2.0, 2.4 Ηζ,ΙΗ), 8.99 (d, 1H, J= 2.0 Hz).
ΥΡ-98 1.25 (t, 7=2.3 Hz, 3H, CH3), 2.56 (q, 7=3.2 Hz, 2H, CH3CH2), 5.46 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.08 (s, 1H, hydrogen on an isoxazole ring), 7.34 (d, 2H, J= 8.0Hz), 7.74 (d, 2H, J= 8.4 Hz), 7.79 (d, 7=2.5 Hz, 1H), 8.26 (d, 7=3.5 Hz, 1H), 8.94 (s, 1H).
ΥΡ-99 1.35 (s, 9H, 3CH3), 5.46 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.08 (s, 1H, hydrogen on an isoxazole ring), 7.38 (d, 2H, 7= 8.0 Hz), 7.72 (d, 2H, 7= 8.4 Hz), 7.79 (d, 7=2.5 Hz, 1H), 8.26 (d, 7=3.5 Hz, 1H), 8.94 (s, 1H).
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YP-100 2.34 (s, 3Η, CH3), 2.56 (s, 6Η, 2CH3), 5.46 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.08 (s, 1H, hydrogen on an isoxazole ring), 6.97 (s, 2H), 7.79 (d, 7=2.5 Hz, 1H), 8.26 (d, 7=3.5 Hz, 1H), 8.94 (s, 1H).
YP-101 3.82 (s, 3H, OCH3), 5.57 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.08 (d, 2H, 7=8.8 Hz), 7.21 (s, 1H, hydrogen on an isoxazole ring), 7.73 (d, 1H, 7=8.4 Hz), 7.85 (d, 2H, 7=8.8 Hz), 8.40 (dd, 1H, J= 2.8, 2.4 Hz), 8.99 (d, 1H, J= 2.0 Hz).
ΥΡ-102 3.82 (s, 3H, OCH3), 5.57 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.01 (s, 1H, hydrogen on an isoxazole ring), 7.05-7.07 (m, 2H), 7.30-7.32 (m, 1H), 7.99 (d, 7=2.1 Hz, 1H), 8.26 (d,7= 1.8 Hz, 1H), 8.32 (d, 7= 2.0 Hz, 1H), 8.94 (s, 1H).
ΥΡ-103 3.82 (s, 3H, OCH3), 5.57 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.01 (s, 1H, hydrogen on an isoxazole ring), 7.02 (d, 7=1.8 Hz, 1H), 7.35-7.40 (m, 3H), 7.79 (d, 7=2.5 Hz, 1H), 8.26 (d, 7=3.5 Hz, 1H), 8.94 (s, 1H).
ΥΡ-104 5.58 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.19 (s, 1H, hydrogen on an isoxazole ring), 7.68 (d, 2H, 7= 8.4 Hz), 7.72 (d, 2H, 7= 8.4 Hz), 7.99 (d, 7=2.5 Hz, 1H), 8.26 (d, 7=3.5 Hz, 1H), 8.94 (s, 1H).
ΥΡ-105 5.58 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.19 (s, 1H, hydrogen on an isoxazole ring), 7.34-7.35 (m, 1H), 7.51-7.52 (m, 1H), 7.61 (d, 7=2.3 Hz, 1H), 7.68 (d, J= 2.3 Hz, 1H), 7.99 (d, 7=2.5 Hz, 1H), 8.26 (d, 7=3.5 Hz, 1H), 8.94 (s, 1H).
ΥΡ-106 5.58 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.22 (s, 1H, hydrogen on an isoxazole ring), 7.30 (d, 2H, 7= 8.4 Hz), 7.79 (d, 7=2.3 Hz, 1H), 8.15 (d, 2H, 7= 8.4 Hz), 8.26 (d, 7=3.5 Hz, 1H), 8.94 (s, 1H).
ΥΡ-107 5.58 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.22 (s, 1H, hydrogen on an isoxazole ring), 7.28-7.29 (m, 1H), 7.49-7.50 (m, 1H), 7.71-7.77 (m, 2H), 7.99 (d, 7=2.5 Hz, 1H), 8.26 (d, 7=3.5 Hz, 1H), 8.94 (s, 1H).
ΥΡ-108 5.61 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CQ), 7.32 (s, 1H, hydrogen on an isoxazole ring), 7.62 (d, 2H, 7= 8.4 Hz), 7.74 (d, 1H, 7= 8.4 Hz), 7.95 (d, 2H, 7=8.4 Hz), 8.41 (dd, 1H, J= 2.4, 2.4 Hz), 9.01 (t, 1H, J= 0.4 Hz).
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YP-109 5.62 (s, 2H, isoxazole-CFF), 6.43 (t, 7=4.6 Hz, 1H, NH-CO), 7.14 (s, 1H, hydrogen on an isoxazole ring), 7.46-7.57 (m, 2H), 7.65 (dd, 1H, 7= 1.2, 1.2 Hz), 7.71 (d, 2H, 7=7.6 Hz), 8.38 (dd, 1H, J= 2.4, 2.4 Hz), 8.97 (d, 1H, J= 2.0 Hz).
YP-110 5.62 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CO), 7.14 (s, 1H, hydrogen on an isoxazole ring), 7.43 (d, 7=2.5 Hz, 1H), 7.50 (s, 1H), 7.99 (d, J=3.2 Hz, 1H), 8.03 (d, 7=3.4 Hz.lH), 8.26 (d, 7=3.5 Hz, 1H), 8.94 (s, 1H).
YP-111 5.67 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CO), 7.38 (s, 1H, hydrogen on an isoxazole ring), 7.79-7.82 (m, 3H), 7.94 (d, 2H, 7=8.8 Hz), 8.47 (dd, 1H, 7=2.4, 2.4 Hz), 9.07 (d, 1H, 7=2.4 Hz).
YP-112 5.62 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CO), 7.14 (s, 1H, hydrogen on an isoxazole ring), 7.46-7.57 (m, 2H), 7.65 (dd, 1H, 7= 1.2, 1.2 Hz), 7.71 (d, 2H, 7=7.6 Hz), 8.38 (dd, 1H, J= 2.4, 2.4 Hz), 8.97 (d, 1H, J= 2.0 Hz).
YP-113 5.62 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CO), 7.14 (s, 1H, hydrogen on an isoxazole ring), 7.40-7.45 (m, 1H), 7.48 (s, 1H), 7.56 (d, 7=2.5 Hz, 1H), 7.72 (d, 7=2.5 Hz, 1H), 7.99 (d, 7=2.5 Hz, 1H), 8.26 (d, 7=3.5 Hz, 1H), 8.94 (s, 1H).
YP-114 5.62 (s, 2H, isoxazole-CH2), 6.43 (t, 7=4.6 Hz, 1H, NH-CO), 7.14 (s, 1H, hydrogen on an isoxazole ring), 7.99 (d, 7=2.5 Hz, 1H), 8.05 (d, 2H, 7=7.6 Hz), 8.26 (d, 7=2.5 Hz, 1H), 8.32 (d, 2H, 7=7.6 Hz), 8.94 (s, 1H).
Embodiment 4 Biological Activity Test
The test of activities against the colorectal cancer cell line HCT-116, the human lung cancer cell line A549 and the breast cancer cell line MCF-7 was conducted by an MTT assay. The specific testing process is as follows:
(1) the lung cancer cell line A549 was plated in a 96-well plate, and cultured in 100 pL of medium until the cells were grown to 90%, added into the wells with 1 pL of the drug (the compound to be tested) at 8 different detection concentrations (respectively of the initial concentration of the drug, 50 pM, 5 pM, 500 nM, 50 nM, 5 nM, 500 pM, and 50 pM) for each drug, each drug concentration being made in triplicate wells. After incubated for 18 h, each well was added with 20 pL of a 5 mg/mL MTT solution as formulated, the medium was aspirated after 4 hours, and each well was added with 150 pL DMSO, and detected for an optical density (OD) value thereof at a wavelength of 595 nm. The negative control was DMSO. The inhibition rate
2019101281 23 Oct 2019 was calculated according to the equation.
OD of negative control - OD of drug
Inhibition rate (%) = X 100
OD of negative control
Its IC50 value was calculated by GraphPad Prism 5 software.
(2) The screening process in the colorectal cancer cell line HCT-116 and in the breast cancer cell line MCF-7 was the same as that in the lung cancer cell line A549.
The activity results of the selected compounds in inhibiting the human lung cancer cell A549, the colorectal cancer cell line HCT-116 and the breast cancer cell line MCF-7 were shown in Tables 3, 4 and 5 below.
Table 3 - Testing results of activities of some example compounds of formula (I) in inhibiting the human lung cancer cell A549
Compound Number IC50 (μΜ) Compound Number IC50 (μΜ)
YP-20 27.6 YP-21 260.3
YP-32 188.4 YP-35 287.7
YP-25 266.5 YP-39 554.5
YP-40 214.3 YP-51 2.1
Gefitinib 21.55
Table 4 - Testing results of activities of some example compounds of formula (I) in inhibiting the colorectal cancer cell line HCT-116
Compound Number IC50 (μΜ) Compound Number IC50 (μΜ)
YP-20 273.3 YP-21 272.6
YP-32 203.3 YP-35 a
YP-25 266.0 YP-39 a
YP-40 273.1 YP-51 188.9
Gefitinib 17.9
“-a” IC50 > 1 x 103
Table 5 - Testing results of activities of some example compounds of formula (I) in inhibiting the breast cancer cell line MCF-7
Compound Number IC50 (μΜ) Compound Number IC50 (μΜ)
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YP-20 106.8 YP-21 110.0
YP-32 a YP-35 177.9
YP-25 163.7 YP-39 191.5
YP-40 173.9 YP-51 135.1
Gefitinib 20.68
“-a” IC5o> 1 x 103
The foregoing illustrates the implementation of the present invention. However, the present invention is not limited to the aforementioned implementation. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and scope of the present invention should be included within the protection scope of the present invention.

Claims (5)

  1. What is claimed is:
    1. A pyridine-2-carboxylic derivative of formula (I), a stereoisomer, racemate, tautomer thereof, or a pharmaceutically acceptable salt thereof, <-R2)„
    Formula (I) wherein:
    Z is selected from O, S, NR3, wherein R3 is hydrogen or a Ci-Ce alkyl;
    Ri is selected from halogen, a Ci-Ce alkyl, a Ci-Ce alkoxy, a halogenated Ci-Ce alkyl, an aryl, an aryloxy, a heteroaryl, a heteroaryloxy, a heterocyclic group, and a heterocyclic oxy group;
    R2 is selected from a Ci-Ce alkyl, a Ci-Ce alkoxy, a halogenated Ci-Ce alkyl, a cyano, and a nitro;
    m is an integer from 0-4; n is an integer from 0-5;
    with the proviso that m and n cannot be 0 at the same time, and when m is 0, R2 is not selected from halogen, a Ci-Ce alkyl, Ci-Ce alkoxy, or when n is 0, Ri is not selected from a Ci-C6 alkyl;
    Preferably, wherein in the formula (I):
    Z is selected from O and NH;
    Ri is selected from fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl, phenoxy;
    R2 is selected from fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, nitro or trifluoromethyl;
    m is an integer of 0, 1 and 2; n is an integer of 0, 1,2 and 3;
    with the proviso that m and n cannot be 0 at the same time, and when m is 0, R2 is not selected from fluorine, chlorine, methoxy, methyl, or when n is 0, Ri is not selected from methyl;
    Further preferably, wherein Ri is a substituent at position 5 and/or position 6 on a 2-pyridyl group;
    preferably, R2 is a substituent at position 4 on a 1-phenyl group;
    Or further preferably, wherein it is selected from any one of the following compounds:
    2019101281 23 Oct 2019
    2019101281 23 Oct 2019
    NO2
    2019101281 23 Oct 2019
    YP-84
    YP-85
    ΥΡ-86
    2019101281 23 Oct 2019
    2019101281 23 Oct 2019
  2. 2. A pharmaceutical composition, comprising a therapeutically effective amount of at least one of the pyridine-2-carboxylate derivative of formula (I), the stereoisomer, racemate, tautomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1;
    Preferably, further comprising at least one pharmaceutically acceptable adjuvant; preferably, the adjuvant is an inert and non-toxic excipient, carrier or diluent.
  3. 3. A pharmaceutical formulation comprising at least one of the pyridine-2-carboxylate derivative of formula (I), the stereoisomer, racemate, tautomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1 or 2;
    preferably, the formulation is a solid oral formulation, a liquid oral formulation or an injection.
  4. 4. Use of at least one of the pyridine-2-carboxylate derivative of formula (I), the stereoisomer, racemate, tautomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1 in preparation of an anticancer drug;
    Preferably, wherein the cancer is a cancer associated with EGFR overexpression and/or hyperactivity;
    preferably, the cancer is selected from: an intestinal cancer, a bladder cancer, an ovarian cancer, a breast cancer, a gastric cancer, an esophageal cancer, a lung cancer, a head and neck cancer, a colon cancer, a pharyngeal cancer and a pancreatic cancer;
    still preferably, the cancer is a non-small cell lung cancer (NSCLC) or intestinal cancer, the intestinal cancer, the breast cancer.
  5. 5. A method for preparing the pyridine-2-carboxylic derivative according to claim 1, comprising the steps of:
    reacting a compound of formula (1-1) with a compound of formula (1-2) to obtain a compound of formula (I), wherein, Ri, R2, Z, m, n independently have the definitions according to any of claims 1-4; and X is selected from a leaving group.
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